The transdermal route of parenteral delivery of drugs provides many advantages, and transdermal systems for delivering a wide variety of drugs or other beneficial agents are described in U.S. Pat. Nos. 3,598,122; 3,598,123; 3,731,683; 3,797,494; 4,031,894; 4,201,211; 4,286,592; 4,314,557; 4,379,454; 4,435,180; 4,559,222; 4,568,343; 4,573,995; 4,588,580; 4,645,502; 4,704,282; 4,788,062; 4,816,258; 4,849,226; 4,908,027; 4,943,435; and 5,004,610, all of which are incorporated herein by reference.
Gestodene is a known orally active synthetic progestogen with a progesterone-like profile of activity. See, U.S. Pat. No. 4,081,537 incorporated herein in its entirety by reference. It is used as an oral contraceptive in combination with certain estrogens.
Oral combination pills and intrauterine devices for purposes of contraception have been well documented for their problems such as inconvenience and side effects. Transdermal delivery of contraceptives as disclosed herein is an attempt to eliminate or reduce those problems.
There are many factors, however, which affect the suitability of an active agent for transdermal administration. These are discussed at length in Knepp et al, "Transdermal Drug Delivery: Problems and Possibilities," CRC Critical Reviews in Therapeutic Drug Carrier Systems, Vol. 4, Issue 1 (1987). When it is desired to deliver more than one active agent from a single transdermal delivery device, the problems associated with achieving a workable multi-drug transdermal device with any specific combination of drugs are even more complex and difficult and can often prove to be insurmountable.
Conventional dosage forms such as tablets or injections can administer a combination of two or more active agents, each at their appropriate dose, merely by appropriate selection of the amount of each agent included in the dosage form. In transdermal delivery devices, however, the total dosage of each agent is not established by the amount of each agent that is in the device. Instead, the total dosage of each agent is the product of its average transdermal administration rate (.mu.g/hr) and the time over which the device is applied, and the average administration rate of an agent from a transdermal delivery device is determined primarily by a combination of factors other than the amount of the agent present in the device.
In order for a transdermal delivery device to be able to administer two or more agents from a common reservoir over the same period of time, the relative permeabilities of each of the agents through the skin and the components of the device must bear the same relationship as their relative dosage or administration rate. Thus, for example, if the dosage of each agent were the same, for example 15 .mu.g/day, each agent would have to have the same overall permeability. If, however, one agent were to be delivered at a dosage of 20 .mu.g/day and the other at 1 .mu.g/day, the overall permeability of one would have to be 20 times greater than that of the other.
The situation becomes even more complicated if permeation enhancers are required to increase the inherent permeability of the skin to one or more of the agents being delivered. Identifying a permeation enhancer that has the ability to selectively increase the permeation of the skin to only one agent or to relatively increase the permeability of the skin to two or more agents in the required relationship could often provide an insurmountable obstacle for any specific combination of agents.
If the problems associated with obtaining the desired relative administration rates of the individual agents to the skin can be solved, other factors remain with which to be dealt. The agents individually, in combination with each other, or in combination with a permeation enhancer, must not cause undue irritation or sensitization when applied topically under occlusion. Materials which individually are not irritating or sensitizing may become so when presented to the skin in combination with each other.
Further, the skin has been recognized as the largest metabolizing organ of the body, larger even than the liver. See, A. Pannatier, et al, "The Skin as a Drug Metabolizing Organ," Drug Metabolism Reviews, Vol. 8, No. 2, pp 319-343(1978). Skin can metabolize agents administered transdermally into inactive or potentially harmful metabolites. Thus, it is necessary that the rate at which each agent is metabolized by the skin and the metabolites produced do not prevent the safe and therapeutically effective transdermal administration of each agent into the bloodstream at the desired administration rate.
Assuming these obstacles can be overcome, it is also important that the agent binding capacity of the skin for each of the agents have the proper relationship. Before transdermal administration of an agent into the bloodstream can commence at a steady state rate, the capacity of the skin below the device to bind the agent must be saturated. The time required to achieve this steady state rate is known as the "lag time" and is a function of the rate at which the agent permeates into the skin and the binding capacity of the skin for that agent. In order for the lag time for both agents to be the same, there must be an inverse relationship between each agent's administration rate and the binding capacity of the skin for each agent.
Thus, while there are numerous combinations of beneficial agents which have been found useful for administration orally or by injection, for example, it is by no means obvious that a particular combination of such agents or other agents could also be safely and effectively administered transdermally.
Another obstacle to be considered is the complexity of a woman's menstrual cycle. The menstrual cycle is the result of a complex feedback system including the sex hormones estrogen and progesterone, the pituitary gonadotropins LH and FSH, and gonadotropin-releasing hormones (GnRH) from the hypothalamus. Estrogen in low concentrations inhibits the production of FSH and GnRH (and so of LH). In high concentrations, estrogen stimulates the production of LH and GnRH (and so of FSH). Estrogen and progesterone together inhibit the production of GnRH.
At the beginning of the menstrual cycle, hormone levels are low, e.g., progesterone is virtually absent and estrogen is low but rising. After the menstrual flow ceases and under the influence of the gonadotropin hormones FSH and LH, an egg cell and its follicle begin to mature. The follicle, as it enlarges, secretes increased amounts of estrogen. The rapid rise in estrogen levels near the midpoint of the cycle triggers a sharp increase in production of LH by the pituitary gland that stimulates the follicle to release the egg cell. Thus, the second week is typified by rapidly increasing estrogen, ovulation and moderate amounts of progestin.
Under the continued stimulus of LH, the cells of the emptied follicle grow producing the corpus luteum, which begin to synthesize significant amounts of progesterone, as well as estrogens. Thus, the third week is typified by the highest amounts of progesterone and moderate estrogens. As the progesterone levels increase, estrogen and progesterone together inhibit the production of GnRH, and of gonadotropin hormones, LH and FSH, from the pituitary. As a result of this drop in the level of gonadotropic hormones, production of ovarian hormones drops. Thus, the fourth week of the cycle is typified by declining estrogens and progesterone, with menses ensuing and the monthly cycle begins again.
A contraceptive cycle of estrogen and progestin can mimic the hormone pattern described above. However, the reproductive tract and other estrogen sensitive organs (skin, bone, vascular, etc.) require low to moderate estrogens, e.g., above the post-menopausal level, but not in the excess found in the menstrual cycle during the phase of follicular growth and ovulation activities. Contraceptively effective hormone therapy is designed to keep the level of ovarian hormones in the blood high enough to shut off production of the pituitary hormones FSH and LH so that ovarian follicles do not open and no ovulation occurs, but lower than the excess levels described above.
U.S. Pat. No. 4,816,258 incorporated herein in its entirety by reference discloses a transdermal delivery system for administering ethinyl estradiol and levonorgestrel, together with a permeation enhancer, as a contraceptive. It has now been found by the present inventors that levonorgestrel, even in the presence of a permeation enhancer such as glycerol monooleate, does not sufficiently transport across human epidermis in vivo to achieve therapeutically (ie, contraceptively) effective levels of the drug in the blood from transdermal systems of reasonable or acceptable size.
Surprisingly, it has now been seen that gestodene, while being approximately equipotent with levonorgestrel when applied orally, acts very differently from levonorgestrel when applied transdermally. Gestodene, unpredictably, has a greatly increased flux in comparison to levonorgestrel. The flux of gestodene is sufficient when applied transdermally to provide blood drug levels in amounts that produce effective contraception at each of the different phases of the menstrual cycle, in marked contrast to levonorgestrel.
Australian Patent No. AU-A-15323/88, incorporated herein in its entirety by reference, discloses a transdermal delivery system for the delivery of estrogens and synthetic gestogens for the treatment of climacteric syndrome (the withdrawal symptoms associated with menopause and caused by estrogen deficiency). The patent makes a general statement that natural gestogens, such as progesterone, do not pass through the skin in amounts sufficient to achieve adequate therapeutic effect using transdermal systems of conventional size but that synthetic gestogens do have sufficient flux. Levonorgestrel (or d-norgestrel) is named in the patent as a synthetic gestogen which can be used in the transdermal system, and norgestrel and norethisterone-17-acetate are named as preferred synthetic gestogens for use in the system. Gestodene is not mentioned as a candidate gestogen. It is to be noted here that a markedly greater amount of a gestogen and, consequently, a greater transdermal flux of the drug, is required for effective contraception than is required for treatment of climacteric syndrome. As discussed previously herein, it has been shown that levonorgestrel, the active enantiomer of the preferred gestogen norgestrel, does not, in fact, have a sufficient flux to provide a contraceptively effective amount of drug in vivo when applied transdermally from a reasonably sized system. Additionally, norethisterone-17-acetate (also known as norethindrone-17-acetate and the only drug for which actual data is presented in the Australian patent) has also been found to have an insufficient transdermal flux from a reasonably sized system to provide sufficient blood levels for effective contraception. These facts show that the broad statement in the Australian patent is not generally true and that sufficient flux of synthetic gestogens, particularly with respect to providing a contraceptive effect, is a continuing problem and cannot be predicted.
U.S. Pat. No. 4,286,592, incorporated herein in its entirety by reference, discloses a transdermal system with a contact adhesive layer, where the adhesive layer controls the rate at which drug is released to the skin.
U.S. Pat. No. 4,379,454, incorporated herein in its entirety by reference, discloses a transdermal system which includes a rate controlling layer for controlling the rate at which an absorption enhancer is released to the skin.
U.S. Pat. No. 4,863,738, incorporated herein in its entirety by reference, discloses glycerol monooleate as a suitable skin permeation enhancer for steroids.
U.S. Pat. No. 4,746,515, incorporated herein in its entirety by reference, discloses glycerol monolaurate as a suitable skin permeation enhancer for steroids.